Abstract

Deregulated inflammation is a serious complication of life-threatening microbial infections, including tuberculosis (TB). The pathological hallmark of TB, the granuloma, is an inflammatory structure crucial for containing infection. However, excessive inflammation in granulomas can cause tissue damage and promote bacterial proliferation and dissemination. The assembly of multiprotein inflammasome complexes is an important trigger of inflammation, but it remains unknown how inflammasome activation impacts TB granuloma progression. Here, by in vivo imaging using the zebrafish TB model, we found that inflammasomes and ensuing pyroptotic cell death of infected macrophages drive granuloma expansion and disease progression. We show that different types of inflammasomes are activated during granuloma formation, with host-protective roles for Asc-dependent inflammasome activation and Il1b secretion. In contrast, an Asc-independent pathway induces macrophage pyroptosis and impairs host resistance. Complementary research in ASC-deficient murine macrophages reveals that extracellular bacterial DNA induces CASP11-dependent pyroptosis in a manner dependent on phagosome permeabilization. Finally, we show that mycobacteria induce pyroptosis to escape from cell-in-cell structures that form within granulomas when living infected cells are engulfed by newly attracted macrophages. This study provides new insights into the role of pyroptosis in TB pathogenesis and unravels a novel link between nucleic acid sensing and CASP11-dependent pyroptosis.

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